Submissions for variant NM_020975.6(RET):c.2657G>A (p.Arg886Gln)

gnomAD frequency: 0.00009  dbSNP: rs373594744

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654581	SCV000776475	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 886 of the RET protein (p.Arg886Gln). This variant is present in population databases (rs373594744, gnomAD 0.03%). This missense change has been observed in individual(s) with Hirschsprung disease, medullary thyroid cancer, and/or pheochromocytoma (PMID: 22648184, 28946813, 33981013). ClinVar contains an entry for this variant (Variation ID: 543745). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneKor MSA	RCV000708758	SCV000822197	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708758	SCV001177161	likely benign	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002284418	SCV002011449	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000708758	SCV002529988	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-20	criteria provided, single submitter	curation
GeneDx	RCV002284418	SCV002574288	uncertain significance	not provided	2022-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with medullary thyroid carcinoma, Hirschsprung's disease, and breast cancer (Carter et al., 2012; Amosenko et al., 2018; Chen et al., 2020); This variant is associated with the following publications: (PMID: 31159747, 28946813, 14633923, 32091409, Amosenko2018[casereport], 22648184)
Fulgent Genetics, Fulgent Genetics	RCV002477456	SCV002800704	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-03-24	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003313129	SCV004012938	uncertain significance	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	2018-07-12	criteria provided, single submitter	research
Baylor Genetics	RCV003459554	SCV004208698	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-08-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004792345	SCV005403619	likely benign	Multiple endocrine neoplasia type 2A	2024-08-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.